Pregnancy as a perturbation principle of the intestinal microbiota in inflammatory bowel disease: a focus on microbe-induced myeloid-derived suppressor-like cells

Introduction

Pregnancy is a physiological condition characterized by a variety of anatomic and functional body changes in several organs. The immune system undergoes extensive changes during normal pregnancy in order to enable fetal tolerance, development and growth. We have shown that this shift towards tolerogenic immune cells like TH2 cells and Myeloid-derived suppressor cells (MDSC) is dependent on pregnancy-induced microbiota changes.

Pregnancy has a complex impact on the disease course of IBD patients, with an increased risk for inflammatory flares during and early after pregnancy (Pedersen et al., 2013). We hypothesize that the pregnancy-induced intestinal microbiota changes result in alterations of the immunological status modulating susceptibility to intestinal inflammatory responses.

Aims

In this project we aim to address microbiota-dependent alterations in immune cell composition during pregnancy. Specifically, we would like to elucidate the metabolic potential of luminal and mucosa associated microbiota affecting MDSC maturation and the inflammatory scenario observed in the intestine of pregnant females. Finally, we aim to understand how these shifts are functionally related to susceptibility to intestinal inflammation. Our goals are:

• to determine the influence of pregnancy and pregnancy-related microbiota shifts on MDSC expansion and their role in murine intestinal inflammation models.
• to understand the role of the IBD susceptibility gene ATG16L1 on MDSC development and pregnancy-related host and microbial dysbiosis and re-biosis processes, and
• to identify bacterial taxa and functions, which are specifically altered in pregnant IBD patients, which may affect MDSC maturation and function. Selected taxa will be tested by gnotobiotic transfer experiments.

Outlook

The project will generate functional hypotheses on potential microbial alterations during pregnancy. As an outlook, we will aim to address the exact bacterial and human metabolites (or other signals) that mediate the immunomodulatory principles of pregnancy via the microbiome. Which exact metabolic principles of the microbiome convey the protective or detrimental effects during pregnancy? Can some of these principles be employed in therapeutic approaches?